Project Summary Uveitis is an inflammatory disease of the eye that if inadequately treated can lead to vision impairment and blindness. Since the 1950's corticosteroids have been used as the main treatment option despite side effects from prolonged usage in severe and chronic uveitis. Research into uveitis has uncovered its underlying autoimmune mechanisms as facilitated by pathogenic lymphocytes and cytokines. We propose using a novel endogenous transcriptional activation technology to drive specific upregulation of the regulatory cytokine IL-10 to create a tolerogenic immune environment within the eye. The therapeutic development strategy leverages this emerging oligonucleotide-based technology coupled with the proven ameliorating properties of IL-10 in uveitis. Our first aim seeks to refine human and mouse IL-10 transcriptional activators to select for the best candidates. Our second aim builds upon the first by measuring in situ expression of IL-10 as upregulated by our therapeutic in the eyes of mice. Our third aim seeks to demonstrate in vivo efficacy in a mouse model of uveitis by decreasing disease upon treatment by our therapeutics candidates. The overall goal of these studies is to provide proof-of-concept and show efficacy by our novel IL-10 transcriptional activator therapeutic in this Phase I proposal and prepare the project for additional research and pre-clinical studies in Phase II.